Novel Lysosomal-Associated Transmembrane Protein 4B-Positive Stem-Like Cell Subpopulation Characterizes High-Risk Colorectal Cancer Subtypes

Abstract

Colorectal cancer (CRC) exhibits substantial intertumoral heterogeneity, largely attributable to multiple tumor stem-like cell populations, whose molecular identities and clinical significance remain incompletely defined. This study delineates tumor-intrinsic stem-like cell diversity and its prognostic implications through single-cell transcriptomic profiling of 171,906 tumor epithelial cells (n = 152), integrated with bulk transcriptomic (n = 1389) and genomic (n = 1077) datasets. Functional validation was conducted via in vitro assays and multiplex immunofluorescence. A previously unrecognized lysosome-associated transmembrane protein 4B-positive (LAPTM4B⁺) stem-like cell cluster was identified, distinct from the classical leucine-rich repeat-containing G-protein coupled receptor 5-positive (LGR5⁺) population. LAPTM4B⁺ cells exhibited MYC pathway activation and 8q chromosomal gains, with preferential enrichment in microsatellite-stable, POLE wild-type, and left-sided tumors. Stratification based on LAPTM4B⁺/LGR5⁺ stem-like cell ratios defined four CRC stem-like subtypes (CSS), with CSS2 (LAPTM4B⁺-dominant) associated with the poorest prognosis (HR = 2.31, p < 0.001). The combined expression of LAPTM4B and LGR5 demonstrated superior predictive power for CRC progression compared to either marker alone (AUC = 0.820 vs. 0.715/0.699), underscoring the synergistic influence of distinct stem-like cell populations on patient outcomes. These findings provide novel insights into CRC heterogeneity and cooperative interactions among diverse stem-like populations shaping disease outcomes.

Keywords

colorectal cancer / leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) / lysosome-associated transmembrane protein 4B (LAPTM4B) / stem-like cells

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